tbuckley/cabot-search huggingface dataset:
Abstract 1882: SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer
Authors: Guangcun Cheng, Yayuan Fu, Hua Zheng, ng Li, Xiaolei He, Xi Jiao, Shuhui Luan, Shuai Wang, Lei Jiang, Wenjing Li, Yun Zhang, Lei Liu, Renhong Tang
Journal: Cancer Research (2023)

Abstract Background: Although advances treatments have significantly improved the survival of patients with gastrointestinal cancer in recent decades, there is still an unmet medical need for more effective treatments. A promising strategy is the use of bispecific antibodies that recruit T cells to kill cancer cells by simultaneously binding to CD3 on T cells and tumor associated antigens. CD3-based T cell engagers are highly potent therapeutic molecules with T cell cytotoxicity activities. But high CRS risk and T cell exhaustion has been observed for high affinity CD3-based T cell engagers in clinicals. Effective and safe use of these therapeutics depends on selective targeting of cancer cells and optimal CD3 affinity. MUC17, a member of the mucin family, is a transmembrane glycoprotein only expressed on the apical membrane of normal gastrointestinal mucosal epithelial cells. MUC17 is overexpressed in 23%-52% of patients with gastric cancer. Compared to the adjacent normal tissues, the expression of MUC17 protein is consistently higher in gastric cancer tissues, suggesting that MUC17 is an attractive therapeutic target for gastric cancer. Method &amp; Results: We created MUC17/CD3 T cell engaging bispecific antibodies by starting with a nanobody humanized from camel and a low affinity CD3 antibody. Here we report the design and the promising preclinical activity of SCR-9171 molecule in vitro and in vivo. SCR-9171 induced T cell activation and had potent cytotoxicity of MUC17 positive tumor cells in vitro. However, the cytokine release was much lower than the positive control, which established with a high affinity CD3 antibody. Importantly, in mouse models with reconstituted human immune cells, SCR-9171 showed strong antitumor efficacy against MUC17-positive tumors through the activation of T cells. Tolerability and pharmacokinetics of MUC17/CD3 bispecific antibody are being assessed in cynomolgus monkey. The results demonstrated that SCR-9171 was well tolerated in a one-month repeat-dose toxicology study at 3mg/kg with no associated clinical signs or changes in body weight. Conclusion: These findings suggest that MUC17/CD3 bispecific antibody is a potential therapeutic molecule for MUC17-positive solid tumor. Citation Format: Guangcun Cheng, Yayuan Fu, Hua Zheng, ng Li, Xiaolei He, Xi Jiao, Shuhui Luan, Shuai Wang, Lei Jiang, Wenjing Li, Yun Zhang, Lei Liu, Renhong Tang. SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1882.
Abstract 1231: A stochastic data-driven model predicts the timing and distribution of the epithelial-mesenchymal transition
Authors: Annice Najafi, Mohit K. Jolly, Jason T. George
Journal: Cancer Research (2023)

Abstract The Epithelial-Mesenchymal Transition (EMT) is a key contributor to cancer metastasis and morbidity. During this process, epithelial cells acquire migratory and stem-like characteristics, which allow them to travel through vasculature and form distant metastases in a secondary organ site via the reverse process of MET. Initially thought of as a binary process, it is now well established that cells can be stably arrested en route to EMT in an intermediate hybrid state (H) with characteristics falling on a spectrum between the epithelial (E) and mesenchymal (M) phenotypes. This non-transient intermediate state is stabilized by phenotypic stability factors and is associated with more tumor aggressiveness, worse treatment response, and patient outcomes. Although abundant time-course single-cell RNA sequencing data exists, enabling dynamical single-cell analysis of EMT, current methods of EMT state inference are optimized on microarray data. Thus, there is a large need for a computational framework that infers and predicts the E, H, and M fractions at transient and steady states from single-cell RNA sequencing data. Here, we introduce a fully stochastic continuous-time Markov model to predict the dynamics of EMT transitions from time-course data. We fit our continuous-time model on a multi-replicate time-course flow cytometry data of MCF10A cell line where TGF is withdrawn at different days following treatment for each replicate. We then demonstrate that our model is extendable to time-course single-cell RNA sequencing data utilizing a novel data-driven pipeline. Our data-driven pipeline infers the three E, H, and M trajectories from time-dependent and dose-dependent single-cell RNA sequencing data. We confirm our trajectories accurately reflect the E, H, and M states via gene-set enrichment analysis. We find the fraction of cells in each state at stationary distribution using our data-driven pipeline and show that they match the predictions of a previous simulation study. By applying the stochastic model to time-course single-cell RNA sequencing trajectories of four cancer cell lines (A549, MCF7, OVCA420, and DU145), we show that the stochastic model accurately predicts context-specific EMT dynamics over time. Our model is the first RNA sequencing-based method for tracking EMT from longitudinal data at the single-cell resolution and therefore is of immediate utility for studying metastatic signatures in cancer. Citation Format: Annice Najafi, Mohit K. Jolly, Jason T. George. A stochastic data-driven model predicts the timing and distribution of the epithelial-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1231.
Abstract 4710: Novel 3D cytotoxicity assay to assess the impact of chimeric antigen receptor (CAR) domain design on the tumor infiltration and cytotoxicity efficacy of CAR T-cell therapies for solid tumors
Authors: Adrian Johnston, Zeqi Wan, Tina Chen, Yeongseo Lim, Cameron Lee, Wenxuan Du, Jude Philip, Denis Wirtz
Journal: Cancer Research (2023)

Abstract CAR T-cell therapy is a popular topic of discussion in and out of the scientific community. Already with multiple therapies FDA-approved for certain blood cancers, focus has rightly shifted toward FDA approval for solid tumor indications. Yet, advancing past clinical trials to FDA approval has yet to occur and has proved challenging. Of course, multiple factors are at play as to why, but we aim to use-in house expertise to elucidate one, namely CAR T-cell tumor infiltration and tissue migration and surveillance efficacy. Migration is a central parameter ignored in traditional 2D cytotoxicity assays, but there is no tumor cell killing by T cells if there is no T cell migration. We developed a novel first-of-its-kind organoid-based 3D cytotoxicity assay using multicompartment organoids and the most abundant extracellular matrix protein in human organs, collagen. We suspend solid tumor organoids in the center of CAR T-cell/collagen gel mixtures that are solidified then imaged in intervals in the span of two weeks by live-cell time-lapse reflection/fluorescence confocal microscopy, after which standard luciferase-based readouts of quantitative specific lysis is determined. Our assay allows high-resolution tracking of CAR T-cell 3D movements through collagen fibers surrounding solid tumor organoids to determine their random and directional migration as well as their surveillance and infiltration of solid tumor organoids. We will describe the differences between currently in clinical trial mesothelin-specific CAR T-cell therapies that differ in their scFv, hinge, transmembrane, and costimulatory domains; and comparing alongside the traditional 2D luciferase-based cytotoxicity assay, we will underline how 3D migration and infiltration around and into mesothelin-expressing ovarian cancer cell organoids allow the determination of CAR T-cell therapy efficacy of different CAR T clones in a lab’s arsenal for a given solid tumor through migration, infiltration, and subsequent cytotoxic capacity that is absent in traditional 2D cytotoxicity assays. CAR T-cell therapy vector design and cloning can thus be tuned for optimal migration and infiltration using our novel 3D cytotoxicity assay. Citation Format: Adrian Johnston, Zeqi Wan, Tina Chen, Yeongseo Lim, Cameron Lee, Wenxuan Du, Jude Philip, Denis Wirtz. Novel 3D cytotoxicity assay to assess the impact of chimeric antigen receptor (CAR) domain design on the tumor infiltration and cytotoxicity efficacy of CAR T-cell therapies for solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4710.
Abstract 491: Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with <i>KRAS</i> mutations
Authors: Young-Ju Kwon, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim, Kyungjin Kim
Journal: Cancer Research (2023)

Abstract Mitogen-activated protein kinase (MEK) inhibitors have shown promising results in KRAS-mutated cancers with constitutive activation of the RAS/RAF/MEK pathway. However, the intrinsic and acquired resistance to MEK inhibitors is frequently observed in clinical trials. Wnt/β-catenin signaling hyper-activation is reported to be responsible for such resistance in colorectal cancer (CRC). Herein, we introduce a novel tankyrase inhibitor STP1002 to revert the intrinsic and acquired resistance to MEK inhibitors in KRAS-mutated CRC. Dual combination of STP1002 and MEK inhibitor synergistically reduced the oncogenic activity of KRAS (G12V or G12D)-mutated CRC cell lines. Data also showed that concomitant treatment with STP1002 and MEK inhibitor dramatically inhibited tumor growth of KRAS (G12V)-mutated CRC xenograft animal models. Moreover, the combination treatment sensitized the acquired MEK inhibitor-resistant CRC cells and suppressed the Wnt/YAP pathway which is the bypass mechanism of MEK inhibitor resistance. Dual combination of STP1002 and MEK inhibitor is a promising candidate to overcome resistance to MEK inhibitors in colorectal cancer with KRAS-G12V/G12D mutations. The phase 1 clinical trial study is ongoing in order to show safety margin. Citation Format: Young-Ju Kwon, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim, Kyungjin Kim. Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 491.
Abstract 5200: Novel Immuno-Oncology drugs evaluation by humanised immune cells and cancer co-inoculated models
Authors: Bin Xie, Xin Hou, Hanglu Chen, Pengfei Yang, Yanbin Zhou, Danyi Wen
Journal: Cancer Research (2023)

Abstract Currently more and more immunotherapeutic drugs and engineered cells have been developed to use human immune system against cancer. While humanized peripheral blood mononuclear cell reconstitution in immune deficient mice is a forward-straight model for evaluating therapeutic antibodies, this conventional model has several drawbacks to hinder its widespread use, including the graft-versus-host-disease happened after one month of reconstitution, insufficient immune cell infiltration from reconstituted circulatory system and hardly retention of functional innate immune cells, such as macrophages and nature killer cells. To overcome this, LIDE has developed a specific human immune cell and cancer cell co-inoculation model. Cancer-priming PBMC and/or its derivates were well mixed with the fresh cancer cells in MatriGel, co-transferring into NCG mice to form a relatively “hot tumor” tissue for immunotherapy, including drugs targeting T cells, dendritic cells and macrophages. Additionally, we also take advantage of human IL15 transgenic mice to study the function of ex vivo expanded NK cells. This novel method has successfully helped evaluate biological function of immune checkpoint blockers and immune agonists in multiple cancers, such as melanoma, breast cancer, lung cancer, hepatocellular carcinoma and ovarian cancer. Citation Format: Bin Xie, Xin Hou, Hanglu Chen, Pengfei Yang, Yanbin Zhou, Danyi Wen. Novel Immuno-Oncology drugs evaluation by humanised immune cells and cancer co-inoculated models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5200.
Abstract 3064: Exosome-based therapeutic strategy for neuroendocrine prostate cancer
Authors: Amritha Sreekumar, Sharanjot Saini
Journal: Cancer Research (2023)

Abstract Background: Therapy-induced neuroendocrine prostate cancer (NEPC) is an aggressive variant of castration-resistant prostate cancer (CRPC) that is increasing in incidence with the widespread use of second generation of androgen receptor (AR)-pathway inhibitors (APIs) such as Enzalutamide (ENZ). NEPC arises from CRPC-Adenocarcinomas (CRPC-Adeno) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED) wherein prostate cancer cells (PCa) undergo a lineage switch. As a result of this lineage switching, PCa cells exhibit neuroendocrine (NE) features, characterized by expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP). Due to lack of AR signaling, these PCa variants are impervious to anti-androgen therapy and constitute an aggressive variant of advanced CRPC with survival times &amp;lt; 1 year. Clinically, NEPC manifests as the presence of visceral metastatic disease including metastasis to liver, lung, central nervous system or bone despite low serum PSA levels. Current therapeutic options for NEPC are limited to highly toxic platinum drugs. The primary objective of our study is to evaluate novel, exosome-based therapies for NEPC. Methods: Exosomes were isolated from HEK-293T cells by ultracentrifugation. Isolated exosomes were characterized by Nanoparticle Tracking Analyses and electron microscopy. These exosomes were engineered to express biotinylated CEACAM-5 antibody on their cell surface. Exosomes were packaged with a combination of drugs (EZH2 inhibitor and AR inhibitor) by sonication. Engineered exosomes were tested in vitro using NEPC cell line NCI-H660 and in vivo using LuCaP 145.1 patient-derived xenograft model. Results: Engineered exosomes reduced the viability of NEPC cells. CEACAM5-labelled exosomes trafficked to tumor cells as CECAM5 is a surface protein expressed by NEPC cells. Conclusions: Engineered-exosome based therapy may provide a new avenue as a targeted therapy for NEPC. Citation Format: Amritha Sreekumar, Sharanjot Saini. Exosome-based therapeutic strategy for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3064.
Abstract 96: Integrated molecular analysis of human dedifferentiated liposarcoma identifies a population of liposarcoma progenitors vulnerable to TGF beta inhibition
Authors: Nadège Gruel, Chloé Quignot, Julien Vibert, Sylvie Bonvalot, Sophie El Zein, Dimitri Tzanis, Sylvain Baulande, Odette Mariani, Joshua Waterfall, Olivier Delattre, Sarah Watson
Journal: Cancer Research (2023)

Abstract Introduction: Dedifferentiated liposarcomas (DDLPS) are the most frequent high-grade soft tissue sarcoma in adults. From a pathological point of view, these tumors are composed of high-grade undifferentiated tumor cells (DD), often showing an abrupt transition from a compartment of well-differentiated adipocytic tumor cells (WD). Tumor cells from both WD and DD compartments are characterized by recurrent MDM2 amplification, but their cellular origin and the molecular mechanisms associated with dedifferentiation are poorly understood. Methods: We performed an integrated molecular analysis of tumors collected from 11 patients undergoing surgery for primary untreated DDLPS. DDLPS tumors were analyzed by single-cell RNA sequencing (scRNAseq) and bulk RNA sequencing on paired WD and DD samples from the same tumors. Results were validated in vitro and in vivo in an additional cohort of human tumors, patient-derived xenografts and DDLPS cell lines. Results: Through RNA-sequencing of 102,753 individual cells from 11 primary DDLPS lesions, major cell clusters were identified based on unsupervised clustering of gene expression profiles and canonical markers. They include 31 tumor microenvironment clusters and 11 tumor cell clusters. A cluster of tumor cells from the WD compartment is characterized by signatures of early adipocytic progenitors, previously identified as TGFβ-dependent, DPP4-positive stromal progenitors. We show that these cells harbor specifically the truncal genomic alterations of the cancer, with further subclonal mutations identifiable in both WD and DD compartments of DDLPS. Furthermore, these cells have multipotent properties and their differentiation towards the adipocytic lineage is inhibited by TGFβ. Treatment of DD tumor cells with TGFβ inhibitors restores their adipocytic phenotype in vitro and in vivo. Conclusion: We provide the first single-cell atlas of human DDLPS tumor and microenvironment and identify a population of adipocytic tumor progenitors at the origin of both WD and DD compartments. This study provides rationale for the development of therapeutic strategies based on TGFβ inhibition in advanced DDLPS. Citation Format: Nadège Gruel, Chloé Quignot, Julien Vibert, Sylvie Bonvalot, Sophie El Zein, Dimitri Tzanis, Sylvain Baulande, Odette Mariani, Joshua Waterfall, Olivier Delattre, Sarah Watson. Integrated molecular analysis of human dedifferentiated liposarcoma identifies a population of liposarcoma progenitors vulnerable to TGF beta inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 96.
Abstract 1291: Signaling pathways modulated by lncRNA UCA1 during anchorage-independent growth in colorectal cancer
Authors: Sophia Leslie, Kyle D. Doxtater, Samantha Lopez, Kristopher Ezell, Adithya Anilkumar, Amayrani Sanchez, Bilal Hafeez, Tamer Oraby, Meena Jaggi, Timothy Loy, Subhash Chauhan, Manish K. Tripathi
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is the second deadliest cancer, and over 40-50% of patients develop metastasis during their fight against the disease. CRC survival rate drops from 90% to 14% when the condition is contained within the colon vs. when found at distant sites within the body. Metastasis is a multistep process and one of the critical steps for cancer cells to acquire anoikis resistance to survive after detachment from the primary sites and travel through the circulatory and lymphatic systems to distant target organs. Thus, understanding the molecular players involved in the anoikis process and metastasis could be vital for improving the survival of CRC patients. The aberrant expression of a long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been identified in CRC. However, its role in metastasis processes is not yet well defined. Our preliminary results in the anchorage-independent growth (anoikis model) demonstrate increased expression of lncRNA UCA1. Moreover, the overexpression of lncRNA UCA1 led to high expression of stemness markers SOX2 and Kaiso, along with increased survival of anchorage-independent cells, which indicates a potential mechanistic role of UCA1 in anoikis resistance. Thus, in this study, we propose elucidating the role(s) of UCA1 and its associated signaling pathways during anoikis resistance. We hypothesize that the overexpression of lncRNA UCA1 enhances CRC metastasis through anoikis resistance-associated signaling pathways. We will utilize Isogenic CRC cell lines SW480 (oncogenic) and SW620 (metastatic) to understand the mechanistic regulation of anoikis resistance. Lentiviral transduced stable overexpression (SW480+UCA1//GFP) and knockdown (SW620+CRISPRgUCA1) cell lines have been utilized for this study. After subjecting these cell lines (along with control) to anchorage-independent growth conditions, cell cycle, pro-survival, anti-apoptotic, stemness, and glucose metabolism factors will be analyzed through RT-PCR, Digital Droplet PCR (ddPCR), western blot, and FACS analyses. Utilizing the same model, we will examine lncRNA UCA1 linked anoikis resistance specific phosphorylation profiles of kinases, their protein substrates using the Proteome Profiler Phospho-Human Phospho-Kinase Array. Citation Format: Sophia Leslie, Kyle D. Doxtater, Samantha Lopez, Kristopher Ezell, Adithya Anilkumar, Amayrani Sanchez, Bilal Hafeez, Tamer Oraby, Meena Jaggi, Timothy Loy, Subhash Chauhan, Manish K. Tripathi. Signaling pathways modulated by lncRNA UCA1 during anchorage-independent growth in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1291.
Abstract 1799: BH3120, a bispecific antibody targeting 4-1BB and PD-L1 simultaneously, stimulates T cells in tumor tissue preferred manner
Authors: Jing Wang, Jun Wang, Yang Liu, Yan Pang, Aihong Zhang, Jie Feng, Aibo Sun, Xiao Ma, Jingmei Cai, Jiangcheng Xu, Jiawang Liu, Kyoungwoo Lee
Journal: Cancer Research (2023)

Abstract BH3120 is a heterodimeric bispecific antibody, designed to target 4-1BB and PD-L1 simultaneously with Pentambody™ platform, to stimulate anti-tumor immune response in a tumor microenvironment (TME) specific manner. BH3120 showed strong antitumor efficacy in multiple tumor models, and combination of BH3120 with a PD-1 antagonist showed synergic effects eradicating tumor. While BH3120 consistently activates T cells, both as a monotherapy and in combination with a PD-1 antagonist, modulation of immune system in the tumor tissue is clearly de-coupled from that in peripheral blood, suggesting reduced risks of immune related adverse events (irAEs) with BH3120. To verify this hypothesis, BH3120 was compared with reference bispecific antibodies. Combination of BH3120 with a PD-1 antogonist does not result in elevation of transaminase enzymes, while the reference bispecific antibodies, when combined with the same PD-1 antagonist, show significant increase of the enzymes and macrophage in liver. In the toxicology studies conducted so far with cynomolgus monkeys, NOAEL of BH3120 was determined to be 200 mg/kg (QW X 5). Citation Format: Jing Wang, Jun Wang, Yang Liu, Yan Pang, Aihong Zhang, Jie Feng, Aibo Sun, Xiao Ma, Jingmei Cai, Jiangcheng Xu, Jiawang Liu, Kyoungwoo Lee. BH3120, a bispecific antibody targeting 4-1BB and PD-L1 simultaneously, stimulates T cells in tumor tissue preferred manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1799.